Wounds created by surgery require understanding, careful management and surgical technique to avoid infection thus enhancing the healing response. This is particularly so of wounds created in the mucosal surfaces, for example the mouth where sterility and effective wound dressing is problematic. Treatment of the skin with an antiseptic prior to surgery is effective in reducing the bacterial load to below critical colonisation levels. Accordingly, infection in surgery can be reduced, for example, by painting the skin with iodine or chlorhexidine solutions prior to making an incision. This is more difficult in the mucosa, particularly the mouth, where secretion of biological fluids such as saliva constantly washes and potentially contaminates a treated area. Therefore, the mouth is prepared for surgery by physically cleaning an area to remove biofilm, with the application of topical antiseptics, generally as a mouthwash.
Antiseptics are used to reduce the levels of microorganisms on the skin and mucous membranes. The skin and the mucous membranes of the mouth, nose, gastro-intestinal and genito-urinary tracts are home to a large number of relatively harmless, commensal microorganisms. However, when the skin or mucous membranes are damaged or breached in surgery, antiseptics can be used to disinfect the area and reduce the chance of infection. The antiseptics include alcohols, quaternary ammonium compounds, iodine and phenol compounds. The alcohols used are commonly ethanol, 1-propanol, 2-propanol or mixtures of these alcohols. Quaternary ammonium compounds include the compounds benzalkonium chloride, cetyl trimethyl ammonium bromide, cetylpyridinium chloride and benzethonium chloride.
A further class of antiseptics is the bis-biguanide compounds. The bis-biguanide compounds are well known compounds whose activity is as a chemical antiseptic. They are known to be effective on both Gram-positive and Gram-negative bacteria. The compound most commonly used is chlorhexidine. It is often formulated in oral rinses and skin cleansers, and is used in small quantities as a preservative. It may also be used orally in gel form. Chlorhexidine has both bactericidal and bacteriostatic mechanisms of action. The mechanism of action is thought to involve membrane disruption. Examples of bis-biguanide compounds and their use as antiseptics are provided by U.S. Pat. Nos. 4,670,592, 4,666,896 and 5,164,107.
Iodine may be used in an alcoholic solution, called a tincture of iodine. Iodine is also used as a complex with povidone, a water soluble polymer containing triiodide ions. Further, antiseptics include octenidine dihydrochloride, a cationic surfactant, phenol, sodium chloride and sodium bicarbonate.
However, antiseptics of the type traditionally used to sterilise wounds are cytoirritants which induce macrophages. Macrophages are cells produced by the differentiation of monocytes in tissues. Macrophages function in both non-specific defence as well as in helping initiate specific defence mechanisms. Macrophages play a critical role in inflammatory and immunological processes, various phenotypes being involved in both damaging inflammation as well as tissue repair. The divergent effects of macrophages may be explained by their classification into two main interchangable groups. M1 macrophages, or classically activated macrophages, are immune effector cells that are aggressive against microbes and can engulf and digest effective cells. M1 macrophages are activated by lipopolysaccharides and interferon-gamma. Alternatively activated macrophages, designated as M2 macrophages, are a phenotypic grouping involved in wound healing and tissue repair as well as turning off damaging inflammatory, immune system activation by producing anti-inflammatory cytokines such as interleukin-10. M2 macrophages however do not impede immune competence i.e. non immunosuppressive but act via non-inflammatory pro-resolving routes; they also possess powerful pain down-regulation properties, the mediators being in the picogram to nanogram range. Cytokines, such as Maresins [macrophage mediator in resolving inflammation] are part of a group of specialized pro-resolving lipid mediators which are actively biosynthetised during the resolution phase of acute inflammation and are potent agonists, controlling the magnitude and duration of inflammation.
Alternatively activated macrophages are activated by interleukin-4. M1 macrophages produce nitric oxide and reactive oxygen species, making them cytotoxic. Furthermore, they secrete high amounts of pro-inflammatory cytokines, for example IL-12, that promote inflammation. Conversely, M2 macrophages produce anti-inflammatory cytokines such as IL-10, thereby reducing inflammation. Alternatively activated macrophages also produce high levels of fibronectin and matrix-associated proteins, and they promote fibrogenesis from fibroblastoid cells. The induction of arginase in these cells may lead to polyamine and proline biosynthesis, promoting cell growth, collagen formation and tissue repair. A wide range of specialized pro-resolving lipid mediators [SPMs] have been identified i.e. they act to restore of tissue homeostasis with the resolution of aggressive inflammation. This process is highly regulated.
Early in the innate immune response, macrophages produce reactive oxygen species and pro-inflammatory cytokines to drive inflammation. At this stage, the macrophages are classically activated macrophages. During resolution of inflammation, they switch to an alternatively activated phenotype and contribute to debris scavenging, angiogenesis and wound healing. Macrophage differentiation can also be skewed during differentiation in vitro through provision of alternative cytokines (IL-10 or IL-12) per the previous discussion.
As antiseptics of the type traditionally used to sterilise wounds are cytoirritants, there is an inherent tension in treating the area around a wound with an antiseptic; the antiseptic will have cytoirritant effect and therefore tend to induce inflammation. Classically activated macrophages will be present in the surgical wound in view of the disruption of the tissue. Thus, the inflammation effect is enhanced and wound healing is slowed when antiseptic is applied. It would be desirable to provide a composition which is effective in preventing sepsis but which does not increase damaging inflammation with enhancement of epidermal and mucosal healing, reduction of pain with resolution of inflammation